Project Summary/Abstract The incidence of brain metastasis from primary breast cancer is steadily increasing with approximately 15% of patients being diagnosed with brain metastasis. This is particularly grim for patients with Triple Negative Breast Cancer whose incidence can reach up to 35% during their lifetime. Progression of disease is associated with many factors including loss of anti-tumor immunosurveillance, which allows growth and metastatic cancer cells. Recent clinical trials examining the potential benefits of immunotherapeutics in these populations have shown limited responses. Therefore, we must develop novel therapeutic strategies to re-store immune cytotoxic cells actions to treat metastasis of breast cancer to reduce disease morbidity and mortality. We have recently published that the receptor CD47 is over expressed in invasive breast cancer. CD47 is a widely expressed receptor essential for the regulation of innate and adaptive immune responses. We recently discovered that blockade of CD47 increases CD8+ T cell infiltration and increases T cell mediated cancer cell cytotoxicity, indicating that targeting CD47 may serve as an immunotherapy to reduce tumor burden. Furthermore, we have shown that these receptors regulates metabolism as a response to stress such as ionizing radiation. This effect on metabolism could also be responsible for allowing T cells to upregulate their metabolism to meet their biosynthetic needs in the harsh conditions of the tumor microenvironment. This would enhance T cell effector function allowing specific cytotoxicity of cancer cells. Our published data shows that blockade of CD47 enhances radiation growth delay in several preclinical models. Our recently published evidence shows that blockade of CD47 reduces metastasis formation in the 4T1 murine breast cancer model. Together this data supports our hypothesis that anti-CD47 immunotherapy could be a treatment for metastatic brain cancer. We propose to study this paradigm with the following specific aims: 1) Determine whether CD47 blockade plus whole brain irradiation inhibits established breast cancer brain metastasis. 2) Determine whether anti-CD47 immunotherapy potentiates abscopal effects of radiotherapy to inhibit metastasis.